In the production of a drug, it is critical to regulate crystal polymorphism of a chemical substance, an ingredient thereof, because differences in crystalline forms greatly affect properties of the drug such as performance of a preparation, bioavailability, and stability as described in the International Conference on Harmonization (ICH) Q6A Guideline, “Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances.”
Patent Document 1 discloses the presence of five crystal polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, crystals A, B, C, D, and G and an amorphous form and a method for producing them. The method for producing crystal polymorphs described here involves the production of each crystal polymorph by adding a predetermined mixed solvent of methanol and water to 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, dissolving the resultant mixture by heating with stirring, cooling the mixture by the addition of water to obtain the predetermined methanol and water composition and temperature, then collecting crystals by filtration, and drying the crystals.
However, effects of the initial concentration presented in the aforementioned invention are only mentioned with regard to chemical purity and yield in the “Disclosure of the Invention,” and the effects on crystal polymorphs obtained are not mentioned.
At the International Symposium on Industrial Crystallization (Sep. 21-25, 1998, Tianjin, China), Kitamura, Hanada, Nakamura, and others showed in “Crystallization and transformation behavior of thiazole-derivative” that, when the time for water addition is markedly changed, in some cases crystal G or a mixture of crystals A and G may be obtained upon crystallization with the methanol-water composition and the temperature that were thought to result in the formation of only crystal A, and that the crystals obtained are converted to crystal D by changing the temperature and then maintaining it with stirring.
In the production of industrially useful crystal A, the possibility cannot be ruled out that crystal G may be incorporated in these conventional methods. Since the time for water addition is restricted in order to prevent incorporation of crystal G, there is also a problem that industrial production is time-consuming.
Meanwhile, Patent Document 2 discloses a method for producing crystal A or G or a mixture of crystals A and G of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, comprising changing the initial concentration and the time for water addition in producing a crystal polymorph by adding water to 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid dissolved in methanol or a mixed solvent of methanol and water.
However, by crystallization using this mixed solvent system, a crystalline form that is not crystal A or a mixture with crystal A was obtained, and crystal A was not stably obtained, when the ratio of methanol to water was 7:3, the solvent composition used in the present invention.
According to the present invention, it was found that crystal A was obtained even in a region off “region I” in Patent Document 1 when a seed crystal of crystal A was used in a region off “region I” under specific conditions. While crystallization using a seed crystal has been achieved using other solvent compositions, there has been no example in which the solvent composition of the present invention was used.
Patent Document 1: International Publication No. WO99/65885
Patent Document 2: Japanese Patent Laid-Open Publication No. 2003-261548